Methods (brief)
In this first iteration of the living systematic review we searched
for randomised controlled trials that compared pro-dopaminergic
interventions to placebo in adults with unipolar depression (i.e. any
standardised measure, above-threshold symptoms on any standardised
measure, or a clinical diagnosis based on any operationalised
criteria).
Eight databases were searched from inception up to the 9th of
November, 2023 (see protocol
for full search strings). Database search results were imported into EPPI-Reviewer and de-duplicated prior to
screening. All steps related to record screening and data extraction
were completed in EPPI-Reviewer.
Titles and abstracts of the identified records were screened by at
least two reviewers (CF, MC, JK, JP). We retrieved the full-texts and
any supporting documents for all records that were not excluded at the
title and abstract screening stage. The full-text screening was
conducted by at least two reviewers (CF, JK, JP, AK, EB). Conflicts at
title and abstract, and full-text screening, were resolved through
discussion between the two reviewers and involvement of a third reviewer
(AC, EGO). Additional information on the full study eligibility criteria
can be found in the pre-published protocol.
Relevant data was extracted using EPPI-Reviewer by at least two reviewers (CF,
CA, EB, JK).
As specified in our protocol,
we focused on:
- anhedonia symptom severity: using anhedonia-specific scales,
anhedonia-specific sub-scales, or individual items focusing on anhedonia
(observer-rated or self-rated). Continuous, primary outcome.
- acceptability: proportion of participants dropping out for any
reason. Binary, secondary outcome.
- tolerability: the proportion of participants dropping out due to an
adverse event. Binary, secondary outcome.
- safety: the proportion of participants reporting specific adverse
events. Binary, secondary outcome.
- anxiety symptom severity: as per observer or self-reported
standardised scales. Continuous, secondary outcome.
For anhedonia and anxiety symptom severity, we extracted outcome data
reported at 8 weeks post-treatment or manipulation. If the information
at 8 weeks was not available, we considered eligible data ranging
between 4 and 12 weeks (with preference to the time point closest to 8
weeks and, if equidistant, the longer outcome). For acceptability,
tolerability, safety and safety (specific adverse events), we extracted
outcome data reported at the end of the studies.
When extracting continuous outcomes we extracted mean and standard
deviation to two decimal places. Where standard error was reported
instead, we converted the value to standard deviation. Baseline and
endpoint values were extracted, where only change in score and baseline
or endpoint was reported, the missing value was calculated by adding or
subtracting the change score to the baseline or endpoint.
When extracting dichotomous outcomes we extracted natural numbers and
where only percentages of participant groups were reported, a value was
calculated and rounded up to the nearest natural number. Adverse events
were extracted using the exact terms they were reported in the included
studies.
We assessed risk of bias with the RoB2 tool (Higgins et al. 2019).
All outcomes for all included studies were assessed by at least two
reviewers (JK, CF, CA, AH) and conflicts were resolved by discussion
between reviewers (Flemyng et al, 2023). To evaluate biases due to
missing evidence and biases across studies, the ROB-ME tool (Page et al,
2023) was used with the same double screening and conflict resolution
process as described above.
Effect sizes were calculated as standardised mean differences (SMDs)
for continuous outcomes (anhedonia and anxiety symptom severity) and
odds ratios (ORs) for dichotomous outcomes (acceptability, tolerability,
and specific-adverse events). We calculated the 95% confidence interval
(CI) around the pooled effect size for each meta-analysis.
Meta-analyses were conducted using a random effects model with the
inverse variance method, using the restricted maximum-likelihood
estimator for tau2 and the Q-Profile method for the
confidence interval of tau2. Confidence intervals were
adjusted using the Hartung-Knapp method. Prediction intervals were
calculated to better report the effect of heterogeneity on the overall
pooled effect.
We conducted a series of sensitivity analyses on the primary outcome.
We aggregated individual participant data (IPD) of randomised controlled
trials on antidepressants in people with depression, performing a series
of random effects network meta-analyses to compare the effects of
pro-dopaminergic and non-pro-dopaminergic pharmacological interventions
on anhedonia.
Subgroup analyses and meta-regressions were also conducted for the
following variables: mean age of participants, mean anhedonia baseline
score, mean anxiety baseline score, sex (proportion of female
participants), and planned treatment duration. This was done using a
mixed-effects model with the estimation of the between-study
heterogeneity tau2 based on the REML method. Meta-regressions
were only conducted for outcomes where data was available from 10 or
more studies.
Summary of evidence tables were constructed for all outcomes
including a summary of the meta-analytic result, biases within-study,
across-study, and due to indirectness.
Please refer to the protocol
and the extended data for more details.
A list of abbreviations can be found towards the end of the
document.
Results
Below are the results of the systematic review and meta-analysis
including a PRISMA flow diagram (Page et al 2021) for details of the
flow of study selection, a table of characteristics for included
studies, risk of bias assessment, forest plots for each outcome with
accompanying descriptive text.

Description of included studies
We identified 61 eligible studies. The study characteristics for
studies that reported anhedonia scores can be found in Table
1 and characteristics of studies that did not report anhedonia
can be found in Table 2. Data from studies contributed
with at least one outcome with quantitative data (total of 9975
participants), which included adults from multiple countries. The mean
age of participants was 42.4 years (range 15 to 72 years), with a mean
proportion of 0.58 female participants (range 0 to 0.86). Included
studies allocated the participants to treatment lasting between 4 to
12.9 weeks (median, 6 weeks).
|
Author (Year)
|
Country
|
Sponsor
|
Arms (in LSR)
|
Setting
|
Condition
|
Treatment duration
|
Intervention group
|
Participants (n)
|
Females (n)
|
Age (mean)
|
Age (SD) or range (specified)
|
Dosage fixed or flexible
|
Intervention format
|
Planned dosage range (min-max mg/day)
|
Delivered dosage range (min-max mg/day)
|
Delivered dosage (mean mg/day)
|
Anhedonia measure
|
Baseline n
|
Baseline anhedonia (mean (SD))
|
Follow-up n
|
Follow-up anhedonia (mean (SD))
|
|
Bymaster (2011)
|
Romania, Serbia, USA
|
DOV Pharmaceuticals, Euthymics Bioscience
|
2
|
Secondary/Tertiary Care
|
Depressive disorder
|
6 weeks
|
Placebo
|
29
|
19
|
49.5
|
6.9
|
Fixed
|
Oral
|
|
|
|
MADRS Anhedonia Factor
|
28
|
13.7 (1.6)
|
26
|
9.3 (1.58)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Amitifadine
|
34
|
25
|
48.2
|
9.4
|
Fixed
|
Oral
|
50mg to 50mg
|
25mg to 50mg
|
|
MADRS Anhedonia Factor
|
33
|
12.8 (2.1)
|
33
|
7.9 (74)
|
|
Hewett (2009)
|
Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland,
Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden
and Mexico
|
GSK
|
2
|
NA
|
Major depressive disorder
|
8 weeks
|
Placebo
|
199
|
142
|
41.8
|
11.56
|
Flexible
|
Oral
|
|
|
|
MEI Total
|
197
|
26.4 (12.79)
|
197
|
17.4 (19.37)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion XR
|
188
|
138
|
41.8
|
11.68
|
Flexible
|
Oral
|
150mg to 300mg
|
NA
|
170.1mg
|
MEI Total
|
187
|
26.8 (12.95)
|
187
|
24.6 (19.69)
|
|
Hewett (2010a)
|
Australia, France, Germany, the Netherlands, Norway, South Africa and
Sweden
|
GSK
|
2
|
NA
|
Major depressive disorder
|
8 weeks
|
Placebo
|
189
|
125
|
44.5
|
10.79
|
Flexible
|
Oral
|
|
|
|
MEI Total
|
186
|
25.3 (12.81)
|
186
|
18.3 (21.95)
|
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
Bupropion XR
|
204
|
127
|
45.6
|
11.76
|
Flexible
|
Oral
|
150mg to 300mg
|
150mg to 300mg
|
180mg
|
MEI Total
|
202
|
27.2 (13.5)
|
202
|
20.8 (21.74)
|
|
Hewett (2010b)
|
Australia, Belgium, Canada, Croatia, Finland, France, Germany, India,
Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia
and United States
|
GSK
|
2
|
NA
|
Major depressive disorder
|
10 weeks
|
Placebo
|
207
|
144
|
71.3
|
5.9
|
Flexible
|
Oral
|
|
|
|
MEI Total
|
204
|
29.5 (15.16)
|
204
|
16.9 (23.42)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion XR
|
211
|
157
|
70.9
|
5.6
|
Flexible
|
Oral
|
150mg to 300mg
|
150mg to 300mg
|
|
MEI Total
|
210
|
29 (13.85)
|
210
|
23.6 (22.89)
|
|
Jefferson (2006)
|
NA
|
GSK
|
2
|
NA
|
Major depressive disorder
|
8 weeks
|
Placebo
|
139
|
96
|
39.8
|
16-69 (range)
|
Flexible
|
Oral
|
|
|
|
IDS-IVR-30 Pleasure scale
|
|
|
137
|
Change from baseline = -3.7 (4.61)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
IDS-C-30 Pleasure scale
|
|
|
133
|
Change from baseline = -5.3 (4.61)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion XR
|
135
|
89
|
40.0
|
20-68 (range)
|
Flexible
|
Oral
|
150mg to 450mg
|
150mg to 450mg
|
|
IDS-IVR-30 Pleasure scale
|
|
|
133
|
Change from baseline = -6.7 (4.61)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
IDS-C-30 Pleasure scale
|
|
|
133
|
Change from baseline = -5.5 (4.61)
|
|
Koshino (2013)
|
Japan, South Korea
|
GSK
|
3
|
NA
|
Major depressive disorder
|
10 weeks
|
Placebo
|
186
|
85
|
37.9
|
11.09
|
Fixed
|
Oral
|
|
|
|
MADRS item 8
|
186
|
3.7 (1.06)
|
186
|
2 (1.45)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 150mg
|
190
|
92
|
36.0
|
10.42
|
Fixed
|
Oral
|
150mg
|
150mg
|
|
MADRS item 8
|
190
|
3.7 (1.16)
|
190
|
2 (1.45)
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 300mg
|
188
|
83
|
37.5
|
10.96
|
Fixed
|
Oral
|
300mg
|
300mg
|
|
MADRS item 8
|
188
|
3.7 (1.09)
|
188
|
2.1 (1.55)
|
Table 1. characteristics of included studies that reported
anhedonia scores. NI=no information available
|
Author (Year)
|
Country
|
Sponsor
|
Arms (in LSR)
|
Setting
|
Condition
|
Treatment duration
|
Intervention group
|
Participants (n)
|
Females (n)
|
Age (mean)
|
Age (SD) or range (specified)
|
Dosage fixed or flexible
|
Intervention format
|
Planned dosage range (min-max mg/day)
|
Delivered dosage range (min-max mg/day)
|
Delivered dosage (mean mg/day)
|
|
A multicentre comparative… (1994)
|
UK
|
NI
|
2
|
NI
|
Major depressive episode
|
6 weeks
|
Placebo
|
54
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Moclobemide
|
56
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
450mg
|
450mg
|
NI
|
|
Agosti (1991)
|
USA
|
NI
|
3
|
Secondary/Tertiary Care
|
Non melancholic chro*c depression
|
6 weeks
|
Phenelzine
|
10
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
60mg to 90mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
NI
|
Placebo
|
23
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Selegiline (L-deprenyl)
|
12
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
40mg
|
40mg
|
NI
|
|
Amsterdam (1989)
|
USA
|
Sanofi Research (partial grant)
|
5
|
NI
|
Major depression
|
4 weeks
|
Minaprine 100mg
|
34
|
12
|
41
|
12
|
Flexible
|
Oral
|
100mg to 400mg
|
NI
|
93mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Minaprine 200mg
|
39
|
25
|
37
|
13
|
Flexible
|
Oral
|
100mg to 400mg
|
NI
|
186mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Minaprine 300mg
|
43
|
22
|
40
|
12
|
Flexible
|
Oral
|
100mg to 400mg
|
NI
|
279mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Minaprine 400mg
|
37
|
22
|
37
|
13
|
Flexible
|
Oral
|
100mg to 400mg
|
NI
|
352mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
37
|
18
|
39
|
13
|
NI
|
Oral
|
NI
|
NI
|
NI
|
|
Amsterdam (2003)
|
USA
|
Somerset Pharmaceuticals, Inc.
|
2
|
Secondary/Tertiary Care
|
Major depressive disorder, single or recurrent episode
|
8 weeks
|
Selegiline
|
149
|
94
|
41.2
|
11.6
|
Fixed
|
Transdermal
|
20mg
|
20mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
152
|
99
|
43.5
|
10
|
Fixed
|
Transdermal
|
NI
|
NI
|
NI
|
|
Bakish (1992)
|
Canada
|
NI
|
2
|
NI
|
Major depressive episode
|
6 weeks
|
Moclobemide
|
58
|
26
|
42
|
10.9
|
Flexible
|
Oral
|
NI to 600mg
|
NI to 600mg
|
492mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
56
|
20
|
44
|
10.7
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
Bellak (1966)
|
USA
|
*MH
|
2
|
Secondary/Tertiary Care
|
Depression
|
4 weeks
|
Placebo
|
25
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Phenelzine
|
25
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
Benes (2011)
|
Germany
|
GSK
|
2
|
NI
|
At least mild depressive symptoms
|
12 weeks
|
Placebo
|
67
|
45
|
59.5
|
11.3
|
Flexible to week 7, then fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Ropinirole
|
198
|
144
|
58.2
|
11.4
|
Flexible to week 7, then fixed
|
Oral
|
0.5 mg to 4 mg
|
NI
|
1.9 mg
|
|
Bodkin (2002)
|
NI
|
Somerset Pharmaceuticals
|
2
|
Secondary/Tertiary Care
|
Major depressive disorder, single or recurrent episode
|
6 weeks
|
Placebo
|
88
|
53
|
43.2
|
10.8
|
Fixed
|
Transdermal
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Selegiline
|
89
|
53
|
41.4
|
10.9
|
Fixed
|
Transdermal
|
20mg
|
20mg
|
20mg
|
|
Botte (1992)
|
NI
|
NI
|
2
|
NI
|
Unipolar depression, neurotic depression
|
6 weeks
|
Placebo
|
24
|
16
|
43.33
|
9.9
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Moclobemide
|
23
|
13
|
51.39
|
12.69
|
Flexible
|
Oral
|
300mg to 600mg
|
200mg to 600mg
|
NI
|
|
Casacchia (1984)
|
Italy
|
NI
|
2
|
Secondary/Tertiary Care
|
Unipolar psychotic depression, neurotic depression
|
4 weeks
|
Moclobemide
|
18
|
8
|
49.5
|
12.8
|
Flexible
|
Oral
|
NI
|
150mg to 450mg
|
297.2mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
16
|
11
|
49
|
11.4
|
Flexible
|
Oral
|
NI
|
150mg to 400mg
|
212.5mg
|
|
Chouinard (1993)
|
Canada, UK
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depressive episode
|
6 weeks
|
Placebo
|
109
|
66
|
40.200000000000003
|
18-64 (range)
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Brofaromine
|
111
|
57
|
41.2
|
18-64 (range)
|
Fixed
|
Oral
|
75mg to 150mg
|
NI
|
NI
|
|
Coleman (1999)
|
USA
|
Glaxo Wellcome Inc.
|
2
|
NI
|
Moderate to severe depression
|
8 weeks
|
Placebo
|
124
|
73
|
38.5
|
18-65 (range)
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR
|
122
|
68
|
38.1
|
18-64 (range)
|
Flexible
|
Oral
|
150mg to 400mg
|
100mg to 365mg
|
290mg
|
|
Coleman (1999)
|
USA
|
Glaxo Wellcome Inc.
|
2
|
NI
|
Moderate to severe depression
|
8 weeks
|
Placebo
|
152
|
92
|
36.700000000000003
|
19-62 (range)
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion
|
150
|
95
|
36.6
|
18-67 (range)
|
Flexible
|
Oral
|
150mg to 400mg
|
NI
|
NI
|
|
Corrigan (2000)
|
USA
|
NI
|
4
|
NI
|
Major depression, single episode or recurrent episode
|
8 weeks
|
Placebo
|
35
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Pramipexole 0.375mg
|
36
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
0.375mg
|
0.375mg
|
0.375mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Pramipexole 1mg
|
35
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
1mg
|
1mg
|
1mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Pramipexole 5mg
|
33
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
5mg
|
5mg
|
5mg
|
|
Croft (1999)
|
NI
|
Glaxo Wellcome Inc.
|
2
|
NI
|
Moderate to severe depression
|
8 weeks
|
Placebo
|
121
|
61
|
37.4
|
19-64 (range)
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR
|
120
|
61
|
35.9
|
19-70 (range)
|
Flexible
|
Oral
|
150mg to 400mg
|
127mg to 361mg
|
293mg
|
|
Davidson (1988)
|
NI
|
Hoffmann La Roche
|
2
|
NI
|
Major or minor depression
|
6 weeks
|
Isocarboxazid
|
68
|
37
|
41.9
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
49.3mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
62
|
35
|
41.9
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
DelBello (2014)
|
USA
|
Somerset Pharmaceutical, Inc.
|
2
|
Secondary/Tertiary Care
|
Moderate or severe Major Depressive Disorder
|
8 weeks
|
Placebo
|
156
|
104
|
14.7
|
1.6
|
Flexible
|
Transdermal
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
12 weeks
|
Selegiline
|
152
|
93
|
14.8
|
1.62
|
Flexible
|
Transdermal
|
6mg to 12mg
|
NI
|
NI
|
|
Feiger (2006)
|
USA
|
Somerset Pharmaceutical, Inc.
|
2
|
NI
|
Moderate or severe Major Depressive Disorder
|
8 weeks
|
Selegiline
|
132
|
81
|
42
|
NI
|
Flexible
|
Transdermal
|
6mg to 12mg
|
6mg to 12mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
133
|
71
|
42
|
NI
|
Flexible
|
Transdermal
|
NI
|
NI
|
NI
|
|
Feighner (1984)
|
NI
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depressive disorder
|
4 weeks
|
Placebo
|
22
|
19
|
49
|
22-78 (range)
|
NI
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion
|
44
|
30
|
43.9
|
20-70 (range)
|
Flexible
|
Oral
|
NI to 600mg
|
300mg to 600mg
|
392mg
|
|
Georgotas (1986)
|
USA
|
NIMH
|
2
|
NI
|
Major depressive disorder
|
7 weeks
|
Placebo
|
28
|
15
|
64.7
|
7.6
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Phenelzine
|
22
|
13
|
65.5
|
4.4000000000000004
|
Flexible
|
Oral
|
NI
|
NI
|
53.90mg
|
|
Giller (1982)
|
USA
|
NIMH, Hoffman-LaRoche
|
2
|
Secondary/Tertiary Care
|
Depression
|
6 weeks
|
Placebo
|
NI
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
73mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Isocarboxazid
|
NI
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
48mg
|
|
GlaxoSmithKline (1980)
|
USA
|
GSK
|
3
|
Community
|
Major depressive disorder
|
6 weeks
|
Bupropion 150-450mg
|
52
|
35
|
36.4
|
21-67 (range)
|
Flexible
|
Oral
|
150mg to 450mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 300-900mg
|
23
|
13
|
37.799999999999898
|
21-62 (range)
|
Flexible
|
NI
|
300mg to 900mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
47
|
31
|
37.4
|
21-60 (range)
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
GlaxoSmithKline (1985)
|
USA, Canada
|
GSK
|
3
|
Secondary/Tertiary Care
|
Depressive disorder
|
4 weeks
|
Placebo
|
43
|
20
|
51.9
|
25-78 (range)
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 300mg
|
45
|
18
|
52.4
|
26-80 (range)
|
Fixed
|
Oral
|
300mg
|
300mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 450mg
|
40
|
18
|
47.5
|
20-73 (range)
|
Fixed
|
Oral
|
450mg
|
450mg
|
NI
|
|
GlaxoSmithKline (1993)
|
USA
|
GSK
|
5
|
NI
|
NI
|
8 weeks
|
Placebo
|
124
|
80
|
40.700000000000003
|
11.6
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 100mg
|
119
|
77
|
39.6
|
11.9
|
Fixed
|
NI
|
100mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 200mg
|
120
|
65
|
39.6
|
10.4
|
Fixed
|
NI
|
200mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 300mg
|
120
|
70
|
39.9
|
11.4
|
Fixed
|
NI
|
300mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 400mg
|
119
|
66
|
38.799999999999898
|
11.7
|
Fixed
|
NI
|
400mg
|
NI
|
NI
|
|
GlaxoSmithKline (1994)
|
USA
|
GSK
|
3
|
Secondary/Tertiary Care
|
Major depressive disorder
|
8 weeks
|
Bupropion 50-150
|
152
|
90
|
39.1
|
12.2
|
Flexible
|
Oral
|
50mg to 150mg
|
50mg to 150mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
154
|
99
|
38.200000000000003
|
11.4
|
NI
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion 100-300
|
150
|
98
|
37.200000000000003
|
11.3
|
Flexible
|
Oral
|
100mg to 300mg
|
100mg to 300mg
|
NI
|
|
Han (2012)
|
South Korea
|
Korea Research Foundation Grant
|
2
|
Community
|
MDD and problematic online game play
|
8 weeks
|
Placebo
|
28
|
0
|
18.100000000000001
|
6.2
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion
|
29
|
0
|
21.2
|
8
|
Fixed
|
Oral
|
150mg to 300mg
|
NI
|
NI
|
|
Iosifescu (2022)
|
USA
|
Xsome Therapeutics
|
2
|
NI
|
Major depressive disorder
|
6 weeks
|
Dextromethorphan- Bupropion
|
156
|
95
|
42.1
|
12.8
|
NI
|
Oral
|
45mg to 105mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
162
|
117
|
41.2
|
13.77
|
NI
|
Oral
|
NI
|
NI
|
NI
|
|
Jarrett (1999)
|
NI
|
NI
|
2
|
Community
|
Major depressive disorder, atypical features
|
8.8 weeks
|
Phenelzine
|
36
|
25
|
38.700000000000003
|
9.7799999999999905
|
NI
|
NI
|
0.85mg/kg to 1mg/kg
|
NI
|
64mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
10 weeks
|
Placebo
|
36
|
22
|
40.299999999999898
|
10.08
|
NI
|
NI
|
NI
|
NI
|
NI
|
|
Kusalic (1993)
|
NI
|
NI
|
2
|
NI
|
Major depressive episode
|
6 weeks
|
Placebo
|
9
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Moclobemide
|
11
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
482.60mg
|
|
Larsen (1989)
|
Denmark
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depressive episode
|
6 weeks
|
Placebo
|
18
|
12
|
57
|
25-76 (range)
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Moclobemide
|
22
|
15
|
51
|
28-70 (range)
|
Flexible
|
Oral
|
NI to 300mg
|
NI to 300mg
|
NI
|
|
Learned (2012a)
|
Australia, Belgium, Bulgaria, Canada, Esto*a, Finland, France, Germany,
India, Poland, Slovakia, and South Africa
|
GSK
|
2
|
NI
|
Major depressive disorder
|
10 weeks
|
Placebo
|
126
|
46
|
41.9
|
11.79
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
GSK372475
|
134
|
51
|
43
|
12.07
|
Fixed
|
Oral
|
1.5mg to 2mg
|
1mg to 2mg
|
NI
|
|
Learned (2012b)
|
Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India,
Italy, and Poland
|
GSK
|
2
|
NI
|
Major depressive disorder
|
10 weeks
|
Placebo
|
156
|
39
|
41.8
|
10.89
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
GSK372475
|
171
|
54
|
42.4
|
11.64
|
Fixed
|
Oral
|
1mg to 1.5mg
|
1mg to 1.5mg
|
NI
|
|
Liebowitz (1984)
|
NI
|
Public Health Service
|
2
|
Community
|
Atypical depression
|
6 weeks
|
Placebo
|
24
|
14
|
37.700000000000003
|
8.9
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Phenelzine
|
15
|
7
|
33.799999999999898
|
9.3000000000000007
|
Flexible
|
Oral
|
15mg to 90mg
|
60mg to 90mg
|
74mg
|
|
Mann (1989)
|
USA
|
Irma Hirschl and Mallinckrodt Foundations
|
2
|
Secondary/Tertiary Care
|
Major depressive episode
|
6 weeks
|
Placebo
|
22
|
17
|
40.200000000000003
|
10.7
|
Flexible
|
NI
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Selegiline
|
22
|
16
|
45.2
|
12.3
|
Flexible
|
Oral
|
NI
|
NI to 50mg
|
NI
|
|
Nair (1995)
|
Canada, Denmark, UK
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depressive episode
|
7 weeks
|
Moclobemide
|
36
|
25
|
67 (median)
|
60-90 (range)
|
Fixed
|
Oral
|
400mg
|
400mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
35
|
25
|
71 (median)
|
62-89 (range)
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Ose (1992)
|
NI
|
NI
|
2
|
NI
|
Major depressive episode
|
4 weeks
|
Moclobemide
|
35
|
21
|
49 (median)
|
24-79 (range)
|
Fixed
|
Oral
|
300mg to 500mg
|
300mg to 500mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
33
|
18
|
50 (median)
|
30-72 (range)
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Parnetti (1993)
|
Italy
|
Gruppo Sanofi
|
2
|
Secondary/Tertiary Care
|
Prolonged depressive reaction
|
12 weeks
|
Minapramine
|
63
|
36
|
71.599999999999895
|
6.5
|
Fixed
|
Oral
|
200mg
|
200mg
|
200mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
67
|
47
|
71.3
|
6.6
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Quitkin (1990)
|
USA
|
*MH; NHCRC
|
2
|
NI
|
Major, minor, or intermittent depression
|
6 weeks
|
Phenelzine
|
33
|
NI
|
38.9
|
NI
|
Fixed
|
Oral
|
90mg
|
45mg to 90mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
34
|
NI
|
30.1
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Raft (1981)
|
USA
|
*H
|
2
|
Secondary/Tertiary Care
|
Depression
|
5 weeks
|
Phenelzine
|
NI
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
90mg
|
30mg to 90mg
|
90mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
NI
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Rampello (1991)
|
Italy
|
NI
|
2
|
Secondary/Tertiary Care
|
Primary major u*polar depression or bipolar affective disorder depressed
|
6 weeks
|
Minaprine
|
10
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
100mg
|
100mg to 200mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
10
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Raskin (1972)
|
USA
|
*MH
|
2
|
Secondary/Tertiary Care
|
Depression
|
5 weeks
|
Placebo
|
111
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Phenelzine
|
110
|
72
|
37 (median)
|
NI
|
Fixed
|
Oral
|
45mg
|
22.5mg to 45mg
|
NI
|
|
Ravaris (1976)
|
NI
|
Public Health Service; Warner Lambert Research Institute
|
3
|
Primary care
|
Depression
|
6 weeks
|
Phenelzine 60mg
|
21
|
NI
|
43.1
|
15.12
|
NI
|
Oral
|
60mg
|
60mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Phenelzine 30mg
|
21
|
NI
|
41.2
|
16.5
|
Fixed
|
Oral
|
30mg
|
30mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
21
|
NI
|
38.9
|
10.1
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Reimherr (1998)
|
USA
|
Glaxo Wellcome Inc.
|
3
|
NI
|
Major depression
|
8 weeks
|
Placebo
|
121
|
69
|
40.200000000000003
|
12.2
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 150mg
|
121
|
86
|
38.299999999999997
|
11
|
Fixed
|
Oral
|
150mg
|
150mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Bupropion SR 300mg
|
120
|
92
|
38.6
|
10.7
|
Fixed
|
Oral
|
300mg
|
300mg
|
NI
|
|
Rickels (1970)
|
USA
|
Public Health Service
|
2
|
Community, Primary care, Secondary/Tertiary Care
|
Moderate depression
|
4 weeks
|
Methylphenidate
|
NI
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
15mg
|
15mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
NI
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Riesenberg (2010)
|
USA
|
Rexahn Pharmaceuticals
|
4
|
NI
|
Major depression
|
8 weeks
|
Placebo
|
21
|
11
|
42.5
|
10.8
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
RX-10100 5mg
|
21
|
11
|
44.8
|
11.9
|
Fixed
|
Oral
|
5mg
|
5mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
RX-10100 10mg
|
16
|
7
|
42.6
|
11.97
|
Fixed
|
Oral
|
10mg
|
10mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
RX-10100 15mg
|
17
|
9
|
39.4
|
11.27
|
Fixed
|
Oral
|
15mg
|
15mg
|
NI
|
|
Robin (1958)
|
UK
|
NI
|
2
|
Secondary/Tertiary Care
|
Depression
|
4 weeks
|
Placebo
|
23
|
13
|
39.5
|
13.9
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Methylphenidate
|
22
|
16
|
37.5
|
11.5
|
Flexible
|
Oral
|
20mg to 40mg
|
NI
|
NI
|
|
Rowan (1980)
|
NI
|
NI
|
2
|
Secondary/Tertiary Care
|
Depression or mixed anxiety/depression
|
6 weeks
|
Phenelzine
|
NI
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
45mg to 75mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
NI
|
NI
|
NI
|
NI
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Tomarken (2004)
|
USA
|
Glaxo Wellcome Inc.
|
2
|
Community
|
Major depression
|
6 weeks
|
Bupropion SR
|
10
|
6
|
39.4
|
9.8
|
Fixed
|
Oral
|
300mg to 400mg
|
100mg to 400mg
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
9
|
6
|
37.5
|
7.8
|
Fixed
|
Oral
|
NI
|
NI
|
NI
|
|
Ucha (1990)
|
NI
|
NI
|
2
|
NI
|
Major depression
|
6 weeks
|
Placebo
|
24
|
13
|
42.2
|
15.1
|
Flexible
|
Oral
|
NI
|
NI
|
5.6 tabs per day
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Moclobemide
|
24
|
16
|
40.5
|
15.6
|
Flexible
|
Oral
|
300mg to 600mg
|
NI
|
405mg
|
|
Versiani (1989)
|
NI
|
NI
|
2
|
NI
|
Major depression
|
6 weeks
|
Moclobemide
|
164
|
124
|
44
|
12
|
Flexible
|
Oral
|
300mg to 600mg
|
NI
|
NI
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
162
|
123
|
42
|
12
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
Versiani (1990)
|
Brazil
|
NI
|
2
|
NI
|
Major depression
|
6 weeks
|
Moclobemide
|
25
|
NI
|
NI
|
NI
|
NI
|
Oral
|
600mg
|
600mg
|
600mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
25
|
NI
|
NI
|
NI
|
NI
|
Oral
|
NI
|
NI
|
NI
|
|
Versiani (1997)
|
NI
|
NI
|
2
|
Secondary/Tertiary Care
|
Dysthymia
|
6 weeks
|
Moclobemide
|
108
|
73
|
41
|
12
|
Flexible
|
Oral
|
75mg to 750mg
|
75mg to 750mg
|
633mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
104
|
71
|
40
|
11
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
White (1984)
|
USA
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depression
|
4 weeks
|
Tranylcypromine
|
63
|
14
|
38
|
NI
|
Flexible
|
Oral
|
30mg to 60mg
|
NI
|
44.4mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
59
|
21
|
39
|
NI
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
Zarate (2006)
|
NI
|
NI
|
2
|
Secondary/Tertiary Care
|
Major depression
|
8 weeks
|
Memantine
|
16
|
9
|
47.1
|
12.3
|
Flexible
|
Oral
|
5mg to 20mg
|
5mg to 20mg
|
19.4mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
16
|
7
|
46.1
|
9.4
|
Flexible
|
Oral
|
NI
|
NI
|
NI
|
|
Zisook (1985)
|
NI
|
NI
|
2
|
Secondary/Tertiary Care
|
Major or minor depression
|
6 weeks
|
Isocarboxazid
|
NI
|
NI
|
NI
|
NI
|
Flexible
|
Oral
|
NI to 80mg
|
NI
|
39.00mg
|
|
.
|
.
|
.
|
.
|
.
|
.
|
.
|
Placebo
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
NI
|
Table 2. characteristics of included studies that did not report
anhedonia scores. NI=no information reported
Primary outcome: reduction in anhedonia scores at 8 weeks (from 4 to
12 weeks)

Figure X Forest plot for symptoms of anhedonia
(primary outcome) comparing pro-dopaminergic interventions vs placebo
for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD:
standardised mean difference, 95%CI: 95% confidence intervals, SD:
standard deviation.
6 studies contributed with data to the meta-analysis with a total of
2076 participants (1140 allocated to pro-dopaminergic interventions, 936
allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with a
SMD of -0.244 (95%CI from -0.456 to -0.031). The study results presented
an I2 value of 67.7% (95%CI from 23.4% to 86.4%) and a
tau2 value of 0.025 (accounting for a 95% prediction interval
from -0.74 to 0.252).
Risk of bias


Evidence for the efficacy of pro-dopaminergic interventions vs
placebo in improving anhedonia was rated moderate for risk of bias. 50%
of the included studies had an overall high risk of bias while the other
50% had moderate risk of bias, primarily due to missing outcome data,
issues with outcome measurement, and selective reporting of findings.
The extent to which the result was affected by across-study biases is
unclear and all included studies were rated at least moderate in domain
5, selection of results. This result was judged to be at moderate risk
of bias due to indirectness as while there was no clear indication of
indirectness in terms of population, comparator, or outcomes, 80% of the
studies measured the same intervention, bupropion.
Sensitivity analyses
We performed a series of random effects network meta-analyses on the
MADRS “inability to feel” item (aggregated IPD from 34 studies, 14054
participants). First, we included all the available studies and compared
all the antidepressants against placebo.

The comparative effect of buproprion versus placebo was -0.12 (SMD,
95%CI from -0.25 to 0.00; 34 studies, 14054 participants), lower than
what we could observe from the retrieved data (random effects pairwise
meta-analysis, bupropion versus placebo): -0.22 (SMD, 95%CI from -0.44
to 0.01; 5 studies, 2020 participants).

We also performed a random effects pairwise meta-analysis of
buproprion versus placebo based on the aggregated IPD, resulting in
estimates comparable to the network meta-analytical model (SMD -0.12,
95%CI from -0.29 to 0.05; 4 studies, 1085 participants).
Finally, we performed a random effects pairwise meta-analysis
including aggregate data from both sources (IPD and retrieved as
aggregated). As three studies (Hewett 2009 - 87997883, Hewett 2010a -
87997755, Koshino 2013 - 87997374) were available in both sources, we
prioritised aggregate IPD over data retrieved as aggregated. The
comparative effect of bupropion versus placebo was -0.19 (SMD, 95%CI
from -0.33 to 0.04; 6 studies, 2489 participants)
Secondary outcome: Reduction in mean anxiety score at 8 weeks (from
4 to 12 weeks)

Figure X Forest plot for symptoms of anxiety
(secondary outcome) comparing pro-dopaminergic interventions vs placebo
for individuals with anxiety at 4-12 weeks (primary timepoint). SMD:
standardised mean difference, 95%CI: 95% confidence intervals, SD:
standard deviation.
11 studies contributed with data to the meta-analysis with a total of
3517 participants (2077 allocated to pro-dopaminergic interventions,
1440 allocated to pill placebo.
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with a
SMD of -0.166 (95%CI from -0.243 to -0.088). The study results presented
an I2 value of 0% (95%CI from 0% to 60.2%) and a
tau2 value of 0 (accounting for a 95% prediction interval
from -0.251 to -0.08).
Risk of Bias


Secondary outcome: Dropouts due to any reason

Figure X Forest plot for dropouts due to any reason
for the comparison of pro-dopaminergic interventions vs placebo at 4-12
weeks. OR: odds ratio, 95%CI: 95% confidence intervals.
50 studies contributed with data to the meta-analysis with a total of
9168 participants (5234 allocated to pro-dopaminergic interventions,
3934 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 0.959 (95%CI from 0.782 to 1.177). The study results presented
an I2 value of 61.7% (95%CI from 48.1% to 71.8%) and a
tau2 value of 0.24 (accounting for a 95% prediction interval
from -1.045 to 0.962).
Risk of bias


Secondary outcome: dropouts due to side effects

Figure X Forest plot for dropouts due to adverse
events for the comparison of pro-dopaminergic interventions vs placebo
at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.
41 studies contributed with data to the meta-analysis with a total of
8473 participants (4831 allocated to pro-dopaminergic interventions,
3642 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.876 (95%CI from 1.407 to 2.501). The study results presented
an I2 value of 34.8% (95%CI from 4.4% to 55.6%) and a
tau2 value of 0.229 (accounting for a 95% prediction interval
from -1.045 to 1.636).
Risk of bias


Secondary outcome: nausea

Figure X Forest plot for nausea for the comparison
of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds
ratio, 95%CI: 95% confidence intervals.
24 studies contributed with data to the meta-analysis with a total of
6489 participants (3620 allocated to pro-dopaminergic interventions,
2869 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.456 (95%CI from 1.182 to 0.584). The study results presented
an I2 value of 27.2% (95%CI from 0% to 55.9%) and a
tau2 value of 0.064 (accounting for a 95% prediction interval
from -0.189 to 0.94).
Risk of bias


Secondary outcome: headache

Figure X Forest plot for headaches for the
comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks.
OR: odds ratio, 95%CI: 95% confidence intervals.
26 studies contributed with data to the meta-analysis with a total of
6527 participants (3663 allocated to pro-dopaminergic interventions,
2864 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.16 (95%CI from 1.03 to 1.307). The study results presented an
I2 value of 0% (95%CI from 0% to 43.2%) and a tau2
value of 0 (accounting for a 95% prediction interval from 0.007 to
0.29).
Risk of bias


Secondary outcome: insomnia

Figure X Forest plot for insomnia for the comparison
of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds
ratio, 95%CI: 95% confidence intervals.
22 studies contributed with data to the meta-analysis with a total of
5875 participants (3253 allocated to pro-dopaminergic interventions,
2622 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.791 (95%CI from 1.424 to 2.251). The study results presented
an I2 value of 5.3% (95%CI from 0% to 37.5%) and a
tau2 value of 0.03 (accounting for a 95% prediction interval
from 0.15 to 1.015).
Risk of bias


Secondary outcome: constipation

Figure X Forest plot for dropouts due to adverse
events for the comparison of pro-dopaminergic interventions vs placebo
at 8 (4-12) weeks. OR: odds ratio, 95%CI: 95% confidence intervals.
19 studies contributed with data to the meta-analysis with a total of
4818 participants (2708 allocated to pro-dopaminergic interventions,
2110 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.551 (95%CI from 1.248 to 1.927). The study results presented
an I2 value of 0% (95%CI from 0% to 48.9%) and a
tau2 value of 0 (accounting for a 95% prediction interval
from 0.182 to 0.695).
There were no significant subgroup differences between participants
assigned to different classes of drug.
Risk of bias


Secondary outcome: dizziness

Figure X Forest plot for dizziness for the
comparison of pro-dopaminergic interventions vs placebo at 8 (4-12)
weeks. OR: odds ratio, 95%CI: 95% confidence intervals.
22 studies contributed with data to the meta-analysis with a total of
5469 participants (2996 allocated to pro-dopaminergic interventions,
2473 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 1.716 (95%CI from 1.322 to 2.227). The study results presented
an I2 value of 25.8% (95%CI from 0% to 56%) and a
tau2 value of 0.08 (accounting for a 95% prediction interval
from -0.103 to 1.183).
Risk of bias


Secondary outcome: dry mouth

Figure X Forest plot for dry mouth for the
comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks.
OR: odds ratio, 95%CI: 95% confidence intervals.
24 studies contributed with data to the meta-analysis with a total of
6308 participants (3431 allocated to pro-dopaminergic interventions,
2877 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed an effect favouring pro-dopaminergic interventions with
an OR of 2.117 (95%CI from 1.679 to 2.67). The study results presented
an I2 value of 36.1% (95%CI from 0% to 61%) and a
tau2 value of 0.08 (accounting for a 95% prediction interval
from 0.126 to 1.374).
Risk of bias


Secondary outcome: vomiting

Figure X Forest plot for vomiting for the comparison
of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds
ratio, 95%CI: 95% confidence intervals.
5 studies contributed with data to the meta-analysis with a total of
962 participants (614 allocated to pro-dopaminergic interventions, 348
allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus
placebo showed a comparable effect not excluding the null effect with an
OR of 1.898 (95%CI from 0.901 to 1.386). The study results presented an
I2 value of 2.2% (95%CI from 0% to 79.7%) and a
tau2 value of 0 (accounting for a 95% prediction interval
from -0.204 to 1.485).
Risk of bias


Reporting bias
Summary of evidence tables
|
Source of evidence
|
Summary of the association
|
Bias due to study limitations (internal validity)
|
Bias due to reporting bias (external validity)
|
Bias due to indirectness
|
Bias due to other reasons
|
|
Pro-dopaminergic intervention. vs placebo in depressed patients with
symptoms of anhedonia
|
N=6, n=2079; random effects: SMD= -0.24, 95%CI: -0.46, -0.03, I2=68%,
t2=0.025
|
Moderate risk: 50% of the studies had an overall high risk of bias (due
to missing outcome data, and issues with outcome measurement and
selective reporting of findings. 50% of studies had a moderate risk of
bias.)
|
Moderate risk: all studies were rated at least some concerns in RoB2
domain 5, selection of results. The impact of the bias on the magnitude
and direction of the effects of pro-dopaminergic agonists is unclear.
|
Moderate risk: 80% of the studies measured the same intervention,
bupropion.For outcomes. 50% of studies measured anhedonia using the MEI,
30% using the MADRS anhedonia item and 20% using the IDS-IVR-30/IDS-C-30
Pleasure Scale No other clear indication of indirectness in terms of
population, interventions, and outcomes.
|
No clear indication of other biases.
|
|
Pro-dopaminergic interventions vs placebo in improving anxiety
|
N=11, n=3517; random effects: SMD=-0.17, 95%CI: -0.24, -0.09, I2=0%, t2
<0.001
|
Moderate risk: 60% of studies were rated moderate risk of bias while 10%
were rated as high risk of bias. This was primarily due to domain 2-
deviation from intended interventions.
|
Moderate risk: 60% of studies were rated moderate risk in domain 5 of
RoB2. The impact of the bias on the magnitude and direction of the
effects is unclear.
|
Moderate risk: 70% of studies contributing to the analysis tested
bupropion
|
No clear indication of other biases.
|
|
Acceptability of pro-dopaminergic interventions vs placebo
|
N=50, n=9159; Random effects: OR=0.91, 95%CI: 0.73, 1.14, I2=72%
t2=0.334
|
Low risk: 10% of studies had an overall high risk of bias, primarily due
to concerns over outcome measurement, while 32% were rated moderate risk
of bias.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included utilised a variety of interventions used in
differing populations in a range of settings.
|
No clear indication of other biases.
|
|
Constipation reported for pro-dopaminergic interventions vs placebo
|
N=19, n=4809; random effects: OR=1.55, 95%CI: 1.25, 1.93, I2=0%
t2=<.001
|
Low risk: 79% of studies were rated as low risk of bias and no studies
were rated high risk of bias.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases
|
|
Dizziness reported for pro-dopaminergic interventions vs placebo
|
N=22, n=5460, random effects OR=1.72, 95%CI: 1.32, 2.24, I2=26% t2=0.08
|
Low risk: 59% of studies were rated low risk of bias and only 5% were
rated high risk of bias.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases
|
|
Dry mouth reported for pro-dopaminergic interventions vs placebo
|
N=24, n=6299, random effects OR=2.12, 95%CI: 1.68, 2.67, I2=36% t2=0.08
|
Low risk: 75% of studies were rated low risk of bias for RoB2 while only
4% were rated high risk of bias.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases
|
|
Headache reported for pro-dopaminergic interventions vs placebo
|
N=26, n=6518, random effects, OR=1.16, 95%CI: 1.03, 1.31, I2=0%
t2=<0.001
|
Low risk: 62% of studies were rated low risk for RoB2 while 27% were
rated as moderate risk with scores of ‘some concerns’ spread out across
domains in no clear pattern.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases
|
|
Nausea reported for pro-dopaminergic interventions vs placebo
|
N=24, n=6480, random effects OR=1.46, 95%CI: 1.18, 1.78, I2=27% t2=0.06
|
Low risk: 71% of studies were rated low risk for RoB2 while 21% were
rated moderate.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases
|
|
Insomnia reported for pro-dopaminergic interventions vs placebo
|
N=22, n=5866, random effects OR=1.80, 95%CI: 1.43, 2.25, I2=5% t2=0.03
|
Low risk: 68% of studies were rated as low risk for RoB2 while 28% were
rated as moderate risk.
|
Low risk: the impact of bias on the magnitude and direction of the
effects of pro-dopaminergic agonists is low.
|
Low risk: studies included in the analysis utilised a variety of
interventions used in differing populations in a range of settings.
|
No clear indication of other biases.
|
|
Vomiting reported for pro-dopaminergic interventions vs placebo
|
N=5, n=962, random effects OR=1.89, 95%CI: 0.90, 4.00, I2=2%
t2<0.001
|
Moderate risk: 80% of studies were rated as moderate risk and 20% as
high risk due to concerns in RoB2 domains 3 (missing outcome data) and 4
(measuring the outcome)
|
Moderate risk: the impact of the bias on the magnitude and direction of
the effects of pro-dopaminergic interventions is unclear.
|
Moderate risk: only 5 studies contributed to the analysis with a
relatively small number of participants. A variety of interventions were
tested.
|
No clear indication of other biases.
|
Abbreviations
CI: Confidence Interval
GALENOS: Global Alliance for Living Evidence on aNxiety
depressiOn and pSychosis
IPD: Individual Participant Data
OR: Odds Ratio
N: number of studies
n: number of participants
NI: No Information
SD: Standard Deviation
SMD: Standard Mean Difference
REML: Restricted Maximum Likelihood
RoB2: Risk of Bias 2
ROB-ME: Risk of Bias for Missing Evidence
Software Used
We used R version 4.3.1 (R Core Team 2023) and the following
packages; meta (Balduzzi, Rucker, and Schwarzer, 2019); dplyr (Wickham
et al, 2023); readxl (Wickham and Bryan, 2023); kableExtra (Zhu,
2024).
References
Higgins, J. P., Savović, J., Page, M. J., Elbers, R. G., &
Sterne, J. A. (2019). Assessing risk of bias in a randomized trial.
Cochrane handbook for systematic reviews of interventions,
205-228.
Flemyng, E., Moore, T. H., Boutron, I., Higgins, J. P.,
Hróbjartsson, A., Nejstgaard, C. H., & Dwan, K. (2023). Using Risk
of Bias 2 to assess results from randomised controlled trials: guidance
from Cochrane. BMJ Evidence-Based Medicine, 28(4),
260-266.
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I.,
Hoffmann, T. C., Mulrow, C. D., ... & Moher, D. (2021). The PRISMA
2020 statement: an updated guideline for reporting systematic reviews.
Bmj, 372.
Page, M. J., Sterne, J. A., Boutron, I., Hróbjartsson, A.,
Kirkham, J. J., Li, T., ... & Higgins, J. P. (2023). ROB-ME: a tool
for assessing risk of bias due to missing evidence in systematic reviews
with meta-analysis. bmj, 383